Baricitinib in the Treatment of COVID-19

*Shubham Atal, Ananyan Sampath, Aditya Banerjee and Ratinder Jhaj*

### **Abstract**

Baricitinib is a novel Janus kinase (JAK) inhibitor which has recently been included in recommendations for treatment of COVID-19. This chapter is focused on discussing the evidence available regarding the safety and efficacy of use of baricitinib alone or in combination with other therapies for treatment of patients with COVID-19. A systematic literature search was conducted for this purpose to find all clinical studies on baricitinib in treatment of COVID-19. A total of 30 studies, including both clinical trials and observational studies were identified, and they have been described briefly. Collation of the results from these observational and interventional studies shows that baricitinib either alone or in combination with other drugs, when used as an add-on to standard therapy, was found to have favorable outcomes in hospitalized patients with moderate to severe COVID-19. Furthermore, ongoing clinical trials indicate that the drug is still under evaluation across the world for its safety and efficacy in COVID-19. The recent approval of baricitinib by the US FDA for treatment of hospitalized adults with COVID-19 accurately reflects the role of the drug in COVID-19. Baricitinib improves clinical outcomes in hospitalized COVID-19 patients, and additional evidence may establish the drug as a standard treatment in such patients.

**Keywords:** JAK kinase inhibitor, baricitinib, COVID-19, SARS-Cov-2, clinical outcomes, mortality

### **1. Introduction**

Since causing an outbreak of a cluster of cases of pneumonia in Wuhan, China, the novel corona virus, named Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), has spread globally to become one of the worst pandemics ever seen by humankind [1, 2]. With multiple 'waves' of the Corona Virus Disease known as COVID-2019 engulfing the world, the medical and scientific communities have focused their efforts on developing effective management strategies especially for hospitalized patients. These efforts have mostly been concentrated on evaluating the antiviral and anti-inflammatory properties of novel or repurposed medications. COVID-19 treatment guidelines from the World health Organization (WHO), the National Institutes of Health (NIH), U.S., the National Institute for Health and Care Excellence (NICE), UK, and regional healthcare authorities such as Indian Council of Medical Research (ICMR) focus on the management of complications, the prevention of progression, and the provision of supportive care with symptomatic treatment based on evidence-based recommendations. A wide variety of clinical trials and observational studies have been conducted worldwide to evaluate treatment effects on survival rates in various severities of COVID-19 patients, as well as to reduction in morbidity in terms of hospitalization, time to recovery, and symptomatic or virological response in patients with less severe illness. COVID-19 treatments still remain limited; include antiviral therapies such as remdesivir, nirmatrelvir-ritonavir, molupiravir, immunomodulators such as corticosteroids, IL-6 inhibitors, and, more recently, specific monoclonal antibodies such as REGN-COV2 (casirivimab and imdevimab combination), regdanvimab, and sotrovimab among others [3–5].

The FDA granted emergency use authorization (EUA) to baricitinib, a novel Janus kinase (JAK) inhibitor, to be used in combination with remdesivir in November 2020 [6], which was later revised to a standalone therapy in adults and children above 2 years of age hospitalized for COVID-19 [7]. Finally, in May 2022, baricitinib has received approval from the FDA for the treatment of COVID-19 in hospitalized adults requiring supplemental oxygen, non-invasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO) [8]. At present, European Medicines Agency (EMA) is evaluating the marketing authorization application for baricitinib to be used in COVID-19 treatment protocol for patients above the age of 10 years of age who require supplemental oxygen therapy [9]. In May 2021, the Central Drugs Standard Control Organization (CDSCO), drug regulatory authority of India also granted emergency use approval to baricitinib for the treatment of confirmed COVID-19 hospitalized adults requiring supplemental oxygen in combination with remdesivir [10]. Baricitinib is an oral JAK 1 and 2 inhibitor that was approved for rheumatoid arthritis in the United States and Japan in 2017 [11]. JAKs are a family of enzyme involved in the inflammatory pathway that helps regulate the signaling cascade, activating signal transducers and activators of transcription (STATs) for cytokines such as IL-2, 6, 10, 12, IFN- etc. JAK inhibitors (JAK i's) have been shown to be clinically useful in immune, inflammatory, and hematopoietic diseases by preventing the dysregulated production of proinflammatory cytokines involved in cellular survival, proliferation, differentiation, and immigration [12, 13]. As a result, baricitinib has been studied in the treatment of COVID-19 with the goal of suppressing the hyperinflammatory state of cytokine release syndrome (CRS) or hypercytokinemia (cytokine storm) associated with COVID-19 [14].

Systematic/living reviews of COVID-19 therapies [15, 16] and JAK inhibitors [17, 18] are available. This chapter solely focuses on a comprehensive synthesis of the evidence available regarding use of baricitinib in treatment of COVID-19. For this purpose, we have used a systematic search strategy as recommended per the Cochrane methodology.

**Figure 1** provides a schematic representation of the mechanism of action of Baricitinib, mainly on three different aspects of Corona Virus Disease, inhibits viral entry, inhibits Inflammation by blocking JAK–STAT signal transduction pathways and alters the immune status via JAK–STAT inhibition.

#### **1.1 Search methodology**

Literature search was conducted to identify studies which assess the efficacy and safety of baricitinib therapy in COVID-19, either alone or in combination with other therapies. This included interventional studies (Randomized Controlled Trials i.e.,

*Baricitinib in the Treatment of COVID-19 DOI: http://dx.doi.org/10.5772/intechopen.107269*

#### **Figure 1.**

*Schematic representation of the mechanism of action of Baricitinib. [1] Interleukins (IL-2, IL-4, IL-7, IL-g, IL-15, IL-21, IL-6) are the most common. Baricitinib inhibits IL-2, IL-4, IL-7, IL-15, IL-21 via JAK1/3 STAT1/3/5 to regulate hemostasis and lymphocyte I proliferation, whereas IL6 acts via tyrosine kinase JAKl/2 STAT3 to regulate T cell differentiation and inflammation. [2] Angiotensin-ACE-2 receptor converting enzyme-2 functions as a docking receptor for SARS C0V-2 attachment. [3] AAKl-adaptor-associated protein I (AAKl-API). [4] Kinase I (AP2-associated protein kinase 1) is a transmembrane enzyme that participates in clathrin-mediated endocytosis. Baricitinib inhibits enzyme activation and thus prevents SARS-CoV 2 endocytosis. [4] Cytokine, type I and type II receptors. [5] Janus activated kinases are intracellular non-receptor tyrosine kinases that regulate cytokine signaling via the JAK–STAT pathway. Baricitinib is a JAK inhibitor that is not selective. [6] Tyrosine residues that aid in the binding of SH2 domain proteins like STAT. [7] Signal transduction activated transcription (STAT) is a downstream transducer of the JAK enzyme that exists intracellularly in an inactivated hypophosporylated state in association with JAK. [8] STAT phosphorylated active form. [9] Specific gene transcription activation. [10] Transcription is followed by protein translation, which results in the regulated effects.*

RCTs and non RCTs) as well as observational studies assessing the efficacy and/or safety of baricitinib in COVID-19, published or pre-published (in English language) after December 2019. Case reports, review articles, conference proceedings, editorial/ comments, author response or book chapter were not included.

The WHO COVID-19 Database (WHO COVID-19 Global literature on Coronavirus Disease) was used which is a comprehensive database of COVID-19 research articles [19] containing global literature from all major standard electronic databases of published, pre-published and gray literature sources such as MEDLINE, Scopus, ProQuest Central, ELSEVIER, Web of Science, EMBASE, ScienceDirect, CINAHL, CAB Abstracts, APA PsycInfo, ChemRxiv, BioMed Central, Oxford Academic, medRxiv, BMC, bioRxiv, etc. Furthermore, a manual search was performed using the bibliography of selected articles, and any studies that satisfied eligibility criteria were added. We searched all information sources up to May 31, 2022.

The list of keywords searched in the Titles, Abstracts and Authors, using Boolean operators consisted of *Baricitinib, Janus Kinase*, *JAK–STAT*, *Therapy*, *Treatment*,

*2019 novel Coronavirus disease*, *COVID-19*, *SARS-CoV-2*, *novel Coronavirus infection*, *2019-ncov infection*, *Coronavirus disease 2019*, *Coronavirus disease-19*, *2019-ncov disease*, *COV*, *Coronavirus*. After removing the duplicate results, the titles and abstracts were independently screened by two sets of reviewers based on the eligibility criteria and then assessed for availability of full texts. Data was then extracted from eligible studies related to pre-decided data items—study characteristics, patient characteristics, interventions studied, and outcomes reported. Standard definitions were used for the severity of disease and various outcome parameters [20].

We used the Cochrane tool for randomized trials (RoB 2.0) [21] to categorize the published RCTs as either low risk of bias, some concerns—probably low risk of bias, more concerns—probably high risk of bias, or high risk of bias. The "Study Quality Assessment tool" [22] was used for critical appraisal of internal validity and bias in observational studies (Non-Randomized Studies of Intervention, NRSIs).

### **2. Evidence from published studies**

After careful consideration, 30 studies were chosen to be described in this chapter. Among these, there are 24 observational studies and 6 interventional studies. **Table 1** summarizes the details of these published/pre-published studies, as well as the assessment of study quality/risk of bias.

#### **2.1 Observational studies**

In a prospective cohort study conducted in Bangladesh, Hasan et al. [23] included 238 patients with severe COVID-19 pneumonia, 122 of whom received baricitinib 8 mg (high dose) and 116 patients received 4 mg (usual dose) orally for 14 days, along with dexamethasone, remdesivir, and enoxaparin/dalteparin. The time to achieve ≥94% oxygen saturation (5 vs 8 days; IQR: 4–5 and 6–9 days respectively, *P* < 0.05) and the need for supplemental oxygen were significantly shorter in the high dose group. Similarly, the need for intensive care unit (ICU) and intubation support was significantly lower in patients receiving the high dose of baricitinib compared to those receiving the usual dose (9 vs 17.2%, *P* = 0.02; 4.1 vs 9%, *P* = 0.001, respectively), as was the 30-day all-cause mortality (3.3 vs 6%, *P* = 0.001). The median duration of hospitalization in the high dose group was also shorter (11 vs 13 days; IQR: 9.5–14 and 10–17.5 days, respectively, *P* = 0.072). Thrombocytopenia and mouth sores were also significantly higher in the high dose group (9.8 vs 2.6% and 2.4 vs 0.8%, respectively). High-dose baricitinib treatment provided significant benefits in terms of survival and other clinical outcomes among patients with severe COVID-19, albeit at a higher risk of thrombocytopenia and mouth sores. The study participants, however, differed in clinical and biochemical parameters at baseline.

The same investigators conducted another prospective study involving 37 adult patients; 17 were assigned to the 'control' (No Loading Dose, NLD) group, while 20 were assigned to the 'case' (Loading Dose, LD) group, where they received an additional 8 mg loading dose of baricitinib orally before receiving 4 mg daily oral baricitinib for 14 days. Tolerability was good in both groups and there were no significant differences in mortality. However, the median time (in days) to reach SpO2 > 95% was relatively shorter in the LD group as compared to NLD [3 (IQR:2–8) vs 4 (IQR:4–5) respectively, *P* = 0.180]. A similar trend was observed for the median time to return to normal breathing [(LD 5(4–5) vs NLD 8 (7–10) days] and the median time spent in the hospital (LD 12 vs NLD



*Baricitinib in the Treatment of COVID-19 DOI: http://dx.doi.org/10.5772/intechopen.107269*



#### **Table 1.**

*Summary of the observational and interventional studies.*

15 days). The NLD group required greater ICU support and mechanical ventilation (29.4% NLD vs 10% LD, *P* < 0.05 and 11.8% NLD vs 5% LD, *P* = 0.141, respectively) [24].

Titanji et al. [25] conducted a retrospective cohort study in 15 patients with moderate–severe COVID-19 pneumonia, treated with oral baricitinib (2–4 mg OD for a maximum of 7 days) and oral hydroxychloroquine (200–400 mg OD) with standard prophylactic treatment of DVT with unfractionated heparin or lower molecular weight heparin (LMWH). The combination therapy showed improved clinical status in 73% of patients in terms of fever and other presenting symptoms, oxygen requirement, and C-reactive protein (CRP) levels, with 80% survival (12/15); three patients died due to underlying pre-existing conditions. With no comparator and concurrent administration of hydroxychloroquine. With a very small study and no comparator, this study could not establish a cause-effect relationship between baricitinib treatment and outcomes.

In Verona, Italy, Bronte et al. [26] observed 76 patients with COVID-19 pneumonia prospectively, 20 of whom received 4 mg BD baricitinib for 2 days as an initial loading dose, followed by 4 mg OD for 5 days as maintenance dose, in addition to standard therapy of hydroxychloroquine and/or antivirals (ritonavir/lopinavir), along with supportive therapy with antimicrobials and anticoagulants. The mortality rate in the baricitinib cohort was significantly lower than in the standard therapy cohort [1(5%) vs 25(45%), respectively]. Similarly, the need for oxygen flow therapy was reduced (*P* < 0.001), as were serum/plasma levels of CRP (*P* < 0.001), p-STAT3 (*P* < 0.001), as well as T lymphocytes, NK cells, monocytes, IL-1, IL-6, and TNF-α concentrations in the baricitinib group. The baricitinib group also showed an absolute increase in circulating lymphocytes, IL-8 serum levels, CD4+ T cells, and an increase in the PaO2/ FiO2 ratio (*P* = 0.02). However, both cohorts faired the same with regards to acute respiratory distress syndrome (ARDS) incidence, hospitalization duration, fever

#### *Baricitinib in the Treatment of COVID-19 DOI: http://dx.doi.org/10.5772/intechopen.107269*

resolution, lung involvement as on HR-CT/Chest X ray, CD8<sup>+</sup> T cells, the absolute number of NK (Natural Killer) cells, and expansion of monocytes.

In a prospective cohort study (with 1:1 matching) in Pisa, Italy, Falcone et al. [27] primarily evaluated the effect of LMWH treatment in 244 patients with COVID-19 pneumonia, as along with assessment of treatment effects of many drugs like hydroxychloroquine, proteases inhibitors, doxycycline, corticosteroids, macrolides, tocilizumab and remdesivir including baricitinib (*n* = 40 patients). Only 21 of these 40 patients, who received baricitinib along with one or more additional drugs, had matched controls and were evaluated for outcome. The univariate and multivariate regression analysis for the association between interventions and mortality revealed a hazards ratio of 0.14 (*P* = 0.006) and an aHR of 0.69 (*P* = 0.45), with a mortality of 9% with baricitinib. The hazards ratio for death/severe ARDS was 0.53 (*P* = 0.12). When baricitinib intervention was matched with mortality and severe ARDS, and regression analysis was performed, the HRs were 1.35 (0.32–5.96) and 1.38 (0.48–4.01), respectively, with *P* values of 0.678 and 0.54. The study found no significant beneficial (or harmful) effect of baricitinib on the clinical recovery of COVID-19 pneumonia patients, but it was clearly underpowered to evaluate the effect of baricitinib.

In a retrospective observational study, Rosas et al. [28] compared the effect of baricitinib and tocilizumab as monotherapies or in combination with the standard of care therapy used for COVID-19 in Spain among 60 patients. The baricitinib group (*n* = 12) received 2 or 4 mg orally, tocilizumab group (*n* = 20) received weight adjusted dose of 400–600 mg, combination group (*n* = 11) received both baricitinib and tocilizumab and a fourth group (*n* = 17) received neither of the therapies. The patients received drugs such as antivirals, azithromycin, hydroxychloroquine, interferon, corticosteroid apart from the above therapies. More than 50% of patients were over the age of 70 years. The study revealed no significant mortality benefits of either of the treatment regimens. When compared to the standard of care group (neither tocilizumab or baricitinib), the baricitinib monotherapy group showed a significant reduction in temperature, CRP, D-Dimer, oxygen saturation, and respiratory rate (*P* < 0.05), and the combination group (tocilizumab + baricitinib) showed a similar but more significant difference (*P* < 0.01). When baricitinib was compared to tocilizumab monotherapy, it showed greater reductions in CRP, D-Dimer, respiratory rate, lymphocytosis, LDH, and temperature. During the study, no relevant side effects were recorded with either of the therapies. Baseline comparison revealed that the patients receiving baricitinib/tocilizumab presented with a more serious (worsened) disease in comparison to those who received neither drug.

Milligan et al. [29] conducted a retrospective longitudinal study in 22 patients with COVID-19 pneumonia and compared the effect of baricitinib (2 mg OD orally for 7 days) to the standard of care (hydroxychloroquine ± ribavirin ± corticosteroids and anticoagulant treatment). The baseline characteristics of the participants differed significantly. The study found clinical improvement in patients receiving baricitinib therapy; 16 patients did not experience disease progression, while the remaining patients died (*n* = 3) or required mechanical ventilation. Prior to the completion of the baricitinib regimen, the oxygen demands of the majority of the patients (77.3%) improved by at least one WHO oxygenation criteria. Ferritin and CRP levels fell significantly from a median of 885 to 326.5 ng/ml and 20.35 ng/ml to 17.3 mg/dl, respectively. Baricitinib caused mild adverse effects such as thrombocytosis (*n* = 22), transaminase elevation (*n* = 5), while acute kidney injury, AKI (*n* = 2), lymphopenia (*n* = 1) led to treatment discontinuations.

Cantini et al. [15] conducted a pilot ambivalent cohort study in Italy, enrolling 12 patients with moderate COVID-19 who received baricitinib in addition to standard antiviral and hydroxychloroquine therapy. Another 12 patients were matched from previous hospital records to serve as controls, who had received the then-standard of care therapy. Overall, clinical characteristics and respiratory function parameters improved significantly in the baricitinib-treated group. CRP levels decreased significantly after 14 days, whereas no significant changes were observed in the controls. While none of the baricitinib-treated patients requested ICU transfer, 33% (4/12) of the controls did (*P* = 0.093). In comparison to 8% (1/12) of the controls, 58% (7/12) of the baricitinib-treated patients were discharged at 14 days (*P* = 0.027). Fever, SpO2, PaO2/FiO2, CRP, and the Modified Early Warning Score (MEWS) all improved significantly when compared to controls.

The same team of researchers also conducted a retrospective longitudinal multicentric study in patients who had previously been hospitalized with moderate COVID-19 to compare the effectiveness of standard therapy (*n* = 78) and baricitinib (*n* = 113) administered over the course of 2 weeks as an add-on to lopinavir/ritonavir and LMWH. The 2-week case-fatality rate was found to be significantly lower in the baricitinib group as compared to the control group (0 vs 6.4% in baricitinib vs control, *P* = 0.01), along with lesser ICU admissions (0.88 vs 17.9%). SpO2, PaO2/ FiO2, transaminase levels, and lymphocyte counts were significantly increased in the baricitinib group, while CRP and IL-6 levels were significantly decreased. At discharge, the baricitinib group had a significantly lower proportion of patients who tested positive for COVID-19 on pharyngeal swabs (2.5 vs 40% in controls) [16].

Santol et al. [30] studied the incidence of COVID-19 pneumonia in patients receiving disease-modifying anti-rheumatic drugs (DMARDs) retrospectively. COVID was contracted by 40 of 820 rheumatic disease patients. Among the three patients were being treated with baricitinib, none developed COVID, indicating that the drug may have a protective effect. The study's major limitations were the very low number of COVID-19 cases and patients receiving baricitinib.

In a Mexican retrospective cohort study [31], Alba et al. compared baricitinib in combination with dexamethasone (*n* = 123) to dexamethasone alone (*n* = 74) among hospitalized patients with severe COVID-19. Overall 30-day mortality was significantly lower in the combination therapy group (20.3%) than in the dexamethasone monotherapy group (40.5%); *P* < 0.05. Combination therapy did not increase the risk of hospital acquired infections.

Another retrospective study from India [32] described the clinical and biochemical parameters of 31 patients with moderate-to-severe COVID-19 who were treated with a combination of baricitinib and remdesivir. At baseline, over 50% of patients were males, diabetic, had at least one comorbidity, and all of them received steroids along with baricitinib and remdesivir. The treatment reduced oxygen requirement over the course of hospitalization (*P* < 0.05), reduced CRP levels from an average of 93.9 to 32.3 (*P* = 0.0001), IL-6 values from an average of 47.5 to 20.8 (*P* = 0.004), and the neutrophil lymphocyte ratio (NLR), with no significant changes in ferritin or D-dimer. The study also performed a subgroup analysis, which showed that oxygen requirement was higher in older age groups, reduced in individuals with comorbidities, absent in those with no comorbidities, and showed a decrease in all survivors. The CRP value, IL-6, NLR, D-dimer and ferritin all showed a similar trend of reduction with treatment in older age groups and comorbidities.

Garcia-Garcia et al. [33] carried out a retrospective cohort study in Spain to compare the effect of IL-1 inhibitor anakinra (*n* = 125) vs baricitinib (*n* = 217) as an add-on

to corticosteroid and standard care therapy in hospitalized patients with COVID-19 pneumonia, and found no differences in mortality (17.6 vs 16.6%). However, a significantly lower proportion of patients receiving baricitinib required invasive mechanical ventilation than those receiving anakinra (4.6 vs 10.4%; *P* = 0.039).

Garcia-Rodriguez et al. [34] in a prospective cohort study, compared improvement in pulmonary function in patients with moderate to severe COVID-19 pneumonia treated with corticosteroids (*n* = 50) vs combination of corticosteroids and baricitinib (*n* = 62), both in addition to lopinavir/ritonavir and hydroxychloroquine. The combination group improved SpO2/FiO2 significantly more than the corticosteroid alone group (mean difference 49; 95% CI 22–77, *P* < 0.001). Similarly, a significantly lower proportion of patients in the combination group required supplemental oxygen at discharge and 1 month (25.8%, 12.9%) compared to those in the corticosteroid alone group (62%, 28%), with ORs of 0.18 and 0.31 respectively.

In a retrospective analysis by Gómez et al. in Spain [35], 43 hospitalized severe COVID-19 patients (SpO2 < 92%) received barictinib 4 mg orally for 5–7 days; Majority (84%) of these patients were additionally administered corticosteroids. On an 8-category ordinal scale, a substantial median clinical improvement of 3 points (IQR 1–4) was noted from day 1 to day 15 (*P* < 0.01). There was no mortality by days 30 and 60, and all participants were discharged with clinical improvement. The median recovery time was 12 days. All clinical measures associated with poor prognosis in COVID-19 showed a substantial improvement (*P* < 0.05), and no noteworthy adverse effects were reported.

In a retrospective cohort study, Abizanda et al. [36] enrolled 328 older adults with moderate to severe COVID-19 pneumonia (*n* = 164 each on baricitinib and propensity score matched controls). They were divided into two groups: <70 years old (*n* = 86) and ≥70 years old (*n* = 78), receiving a mean total dose of 17.6 ± 10.2 mg baricitinib for a mean 5.9 days of treatment. A few participants were also given tocilizumab, anakinra, and corticosteroids. When using Cox proportional hazard models adjusted for important covariates, patients in the ≥70 age group had a significantly lower 30-day fatality rate with baricitinib (HR 0.21; 95% CI 0.09–0.47; *P* < 0.001). Despite a higher disease severity in the baricitinib group, similar results were found in those <70 (HR 0.14; 95% CI 0.03–0.64; *P* = 0.011). This study demonstrated baricitinib's clinical utility and safety in the important subset of elderly patients.

Thoms et al. [37], in their retrospective longitudinal study in the U.S., observed the impact of short course baricitinib therapy (4 mg daily either as single dose or two divided doses) in 45 COVID-19 positive in-patients in addition to IV remdesivir with a loading dose of 200 mg and 100 mg maintenance dose for 4 days along with dexamethasone 6 mg IV for 10 days. The patients had an average age of 65 years with a predominance of female gender. The average treatment duration was 6 days. Results showed a 4.4% mortality over the first 7 days of admission and 13.3% over the entire duration of hospitalization among patients, with oxygen supplementation in some format required for all participants. There was a reversal in the downward trend of hemoglobin levels post commencement of treatment along with CRP, D-dimer, and ferritin, and along with increased platelet counts. The Adaptive COVID-19 Treatment Trial—Clinical Status (ACTT-CS) scores also showed a significant statistical improvement in response to therapy. Four patients were reported to have experienced a hemodynamic shock requiring a vasopressor.

Gutierrez et al. [38] conducted a case control study in New York city consisting of 139 COVID patients, and compared the effect of dexamethasone 6 mg OD with remdesivir 200 mg IV followed by 100 mg daily IV for 10 days (Standard of Care,

SOC) and a combination of baricitinib 4 mg OD with remdesivir for 10 days. The SOC group consisted of 51 individuals serving as controls, and 88 patients who received SOC plus baricitinib were considered as cases. The groups displayed similar baseline characteristics. Thirty-three patients received mechanical ventilation overall, of which 14 were in standard therapy (27.45%) and 19 (21.59%) in the baricitinib group. There was an increased need for antibiotics in the controls over the cases (76.5 vs 53.4%, *P* = 0.007). The individuals who received baricitinib displayed a reduction in median time to recovery by 3 days compared to the control group, but this difference was not statistically significant. The study also performed stratification based on oxygen requirement, and those with low flow oxygen (OS5) and high flow nasal cannula (OS6) both showed significant reductions in median time to recovery (OS 5: 3 days lesser, rate ratio of recovery of 2.95 in 95% CI, 1.03–8.42, *P* = 0.04, OS 6: 2 days lesser, Rate Ratio 1.80, 95% CI, 1.09–2.98, *P* = 0.02).

Tanimoto et al. [39], in their propensity score-matched retrospective cohort study, recruited 229 patients in Hiroshima, Japan, to study the effect of baricitinib in comparison to standard of care on 30 and 60 day survival after admission. Other drugs such as favipiravir, corticosteroids, remdesivir, heparin and tocilizumab were also administered to both groups in similar proportions. A logistic regression model was used to designate two propensity matched cohorts of similar age, sex, severity of disease, BMI, comorbidities, and usage of other drugs. The 30-day survival was significantly higher in the baricitinib propensity score-matched cohort (*P* = 0.03) whereas there was no significant statistical difference in the 60-day survival. Other outcomes of significance were the need for oxygen therapy in the cohorts where a smaller proportion of individuals in the baricitinib group required oxygen (*P* < 0.001), and a better outcome at discharge in the baricitinib cohort (*P* = 0.02). There were no significant differences in the adverse events reported in either group.

Yasuda et al. [40] carried out a single centre retrospective study in Osaka, Japan, where they recruited 108 COVID-19 positive patients. Of them, 16 were treated with dexamethasone only (6 mg daily for 10 days), 2 with standard of care, 30 received the combination of 3 drugs (baricitinib 4 mg or 2 mg for 2 weeks or until no more requirement of oxygen therapy with dexamethasone and remdesivir IV with a loading dose of 200 mg and maintenance dose of 100 mg for 5 days), and 60 with only remdesivir and dexamethasone (controls). At baseline, the baricitinib group had significantly younger individuals (*P* = 0.006), as well as significantly more severe chest X ray abnormalities (*P* = 0.0248). Patients in the baricitinib group experienced a faster recovery (3 days less, *P* < 0.001), with a recovery rate of 90% in the baricitinib group and 63.3% in the control group (*P* = 0.011). All-cause mortality was also significantly lower in baricitinib (6.7 vs 28.3%, *P* = 0.0263), with a ratio of recovery at 5.26 (95% CI, 1.99–13.9, *P* < 0.001). Among the 39 patients receiving oral anticoagulants, the recovery rate was 90 vs 44.4% (baricitinib vs control, *P* = 0.0089). The study identified age and anticoagulants to be significantly associated with recovery time. Baricitinib showed an accelerated recovery in patients aged 65 years or above (*P* = 0.039) but no such difference in those below 65 years of age (*P* = 0.307).

So et al. [41], in their retrospective cohort study, included 100 COVID-19 diagnosed patients in Southern California, U.S., to compare the efficacy of baricitinib in comparison to other treatment regimens used in the hospital. Those who received baricitinib were *less likely* to be in the intensive care units as compared to those who did not (45.8% of ICU patients took baricitinib and 56.2% did not, *P* = 0.017). Kaplan–Meier analysis revealed that patients who received baricitinib have an increased survival as compared to those who did not (26 days, 95% CI 11.7–40.3, vs

#### *Baricitinib in the Treatment of COVID-19 DOI: http://dx.doi.org/10.5772/intechopen.107269*

14 days, 95% CI 12.4–15.6, *P* = 0.045). The study also revealed that 33% of patients on baricitinib showed an elevation of liver enzymes post commencement of drug administration but not severe enough to indicate an abrupt discontinuation of treatment and returned to normal after stopping treatment.

Bryushkova et al. [42], in their retrospective cohort study on 154 COVID-19 patients in Moscow, Russia, compared the effects of three drugs namely baricitinib, netakimab and tocilizumab along with the standard of care including hydroxychloroquine (400 mg BD on day 1 and 200 mg BD on days 5–10), azithromycin (500 mg once per day for 5 days), lopinavir–ritonavir (400/100 mg twice per day for 14 days), and low molecular-weight heparin according to indications. The cohorts consisted of 38 individuals who received baricitinib, 48 received netakimab, 34 received tocilizumab and 34 received only the standard of care, and showed significant baseline differences in neutrophil lymphocyte ratio, lactate dehydrogenase (LDH) and NEWS-2 median score among the cohorts. The CRP and LDH levels showed significant reduction in the tocilizumab group and netakimab group but not in baricitinib and SOC after 72 h; reduced in all groups majorly after 120 h. In similar trends, NEWS-2 score improved in 72 h for tocilizumab and netakimab, and in 120 h for tocilizumab, netakimab and baricitinib. The NLR showed a decrease in the baricitinib group but an improvement in netakimab and tocilizumab groups. In comparison to the baricitinib (31.6%) and SOC (23.5%) groups, the proportion of patients who were discharged 5–7 days after the initiation of therapy was greater in the tocilizumab (44.1%) and netakimab (41.7%) groups. The SOC (9%) and baricitinib (3%) groups had greater mortality rates than tocilizumab (0%) and netakimab (0%) groups.

A retrospective cohort study conducted by Tziolos et al. [43] in Athens, Greece assessed the role of baricitinib (4 mg/day for 14 days or discharge) as an add-on therapy to the standard of care in 369 hospitalized patients with COVID-19 which included dexamethasone (6 mg/day), remdesivir (200 mg/day on day 1 followed by 100 mg/day for subsequent days) and low molecular weight heparin for thromboprophylaxis apart from antimicrobials as per the physicians discretion. The standard of care regimen was provided to 47.7% of the patients and the remaining received baricitinib as an add-on. At baseline, patients in the standard of care group showed increase comorbidities of hypertension, CVD, heart failure, end stage renal disease (ESRD) and active neoplastic or inflammatory disease and those in the baricitinib group were significantly younger (61.6 ± 12.7 vs 69.1 ± 13.5 years, *P* < 0.001), received remdesivir more often, and an intermediate dose of LMWH and oxygen by high flow nasal cannula (*P* < 0.05 for both). The baricitinib combination showed a reduced overall mortality (14.7 vs 26.6%, *P* = 0.005), achieved a lower composite outcome of ICU admission and all-cause mortality (22.3 vs 36.9%, *P* = 0.002). When subgroup analysis as per ARDS severity was performed, the mortality, and the composite outcome was statistically significant in favor of the combination group for both subgroups. No significant difference in thromboembolic events were seen in either group.

Hasan et al. [44], in their third published study on use of baricitinib in COVID-19, conducted a prospective cohort study in 103 adult patients who were divided into two groups by simple random sampling as 49 participants in group A (receiving baricitinib 4 mg OD PO for 14 days plus secukinumab two doses 48 h apart 300 mg IV) and 54 participants in group B (baricitinib plus secukinumab single dose in similar doses as A plus tocilizumab 8 mg/Kg single dose IV). All patients received dexamethasone 0.25 mg/Kg in divided doses, remdesivir 200 mg IV loading plus 100 mg maintenance for 10 days IV, LMWH, and antimicrobials for infections. The number of male

patients in both groups was higher and the median time of hospitalization was 7 and 9 days in group A and B respectively. Group B showed a quicker median day to achieve normal SpO2, lower requirement of ICU and mechanical ventilation (N = 54) 28.6%/16.7% (*P* = 004); 18.4%/11.1% (*P* = 038), lower risk of ARDS (OR = 0.43, *P* = 0.045) and a lower 60 day all-cause mortality 14.29% (N 1/4 49) vs 7.41% (N 1/4 54); OR 0.35 (0.08–1.44), 95% CI). However, group B also showed a higher rate of adverse events.

#### **2.2 Interventional studies**

Marconi et al. [45] published the findings of the phase 3 COV BARRIER trial, a randomized placebo-controlled double blind study that enrolled adult hospitalized symptomatic COVID-19 patients who required low flow oxygen and had atleast one elevated inflammatory marker (CRP, D-dimer, LDH, ferritin). This trial was carried out at 101 sites in 12 countries across South and North America, Europe, and Asia. It enrolled a total of 1525 participants who received either oral baricitinib 4 mg (*n* = 764) or placebo once daily for 14 days (1:1), in addition to standard of care (SOC), which included low dose systemic corticosteroids (79.3%, mostly dexamethasone), remdesivir (18.9%), and anticoagulants. All patients were monitored for disease progression and mortality until day 28 and then again until day 60. No significant difference was seen in the proportion of patients who progressed (requiring high flow oxygen, non-invasive/invasive ventilation, or death) after treatment with baricitinib vs placebo [27.8 vs 30.5%; OR 0.85, 95% CI 0.67–1.08; *P* = 0.18] on day 28. However, in a prespecified secondary endpoint analysis, baricitinib significantly reduced the all-cause mortality on day 28 compared to placebo (8.1 vs 13.1%, HR 0.57, 95% CI 0.41–0.78, *P* = 0.0018). On day 60 also, mortality was reduced significantly (HR 0.62, 95% CI 0.47–0.83, *P* = 0.005). The survival benefits were more pronounced in patients with more severe disease at baseline. There were no appreciable differences in treatment-emergent adverse events (44.5 vs 44.4%), serious adverse events (14.7 vs 18%), serious infections, or venous thromboembolic events between baricitinib vs placebo. The trial showed that the combination of baricitinib and corticosteroid therapy significantly lowers mortality among patients of moderate—severe COVID-19 who are hospitalized.

The results of the first stage of the Adaptive COVID-19 Treatment Trial (ACTT-1) demonstrating the efficacy of remdesivir treatment in hospitalized COVID-19 patients with pneumonia were released in May 2020 [46]. In ACTT-2 [47], the efficacy of treatment with remdesivir in combination with baricitinib was compared to remdesivir plus placebo (control) in 1033 hospitalized adults with COVID-19. The combination group patients (*n* = 515) were given oral baricitinib at a daily dose of 4 mg for 14 days, or until hospital discharge/death along with IV remdesivir in a loading dose of 200 mg on day one, followed by a maintenance dose of 100 mg from day 2 to day 10, or until hospital discharge/death Patients who got remdesivir in combination with baricitinib had quicker recovery than those who received only remdesivir (median 7 vs 8 days; RR for recovery 1.16; 95% CI 1.01–1.32; *P* = 0.03). The combination group had a faster median time to recovery of 10 days compared to 18 days among patients getting high flow oxygen or non-invasive ventilation (RR 1.51; 95% CI 1.10–2.08). The RR of recovery was 0.88 (95% CI 0.63–1.23), 1.17 (95% CI 0.98–1.39) and 1.08 (95% CI 0.59–1.97) for patients who received no oxygen, supplemental oxygen, and mechanical ventilation respectively. After 28 days, the overall mortality rate was relatively lower in the combination group (5.1 vs 7.8%, HR 0.65;

#### *Baricitinib in the Treatment of COVID-19 DOI: http://dx.doi.org/10.5772/intechopen.107269*

95% CI 0.39–1.09). Patients who received supplemental oxygen had a relatively lower mortality rate than those who received high flow oxygen (1.9 vs 4.7%; HR 0.40; 95% CI 0.14–1.14 or non-invasive ventilation (7.5 vs 12.9%; HR 0.55; 95% CI 0.22–1.38), but results were not statistically significant. Patients in the combination group recovered in 6 days on an average compared to 8 days in the control group (RR 1.21; 95% CI 1.06–1.39). In the combination group, 40.7% (*n* = 207) patients experienced grade 3 or 4 adverse events (anemia, hyperglycemia, decreased lymphocyte count, and acute kidney injury), compared to 46.8% (*n* = 238) patients in the remdesivir group. Among these, a significantly higher proportion of patients experienced serious adverse events in the remdesivir group (21%) compared to the combination group (16%); a difference of −5.0% (95% CI, −9.8 to −0.3; *P* = 0.03). This trial concluded that baricitinib in combination with remdesivir is superior and safer than remdesivir alone, with fewer serious adverse events. Combination therapy also helps patients recover faster and accelerates improvements in clinical status, especially among those who require high flow oxygen or non-invasive ventilation.

A small interventional study was conducted by Izumo et al. [48] in Tokyo, Japan, on COVID-19 patients with severe or critical disease without renal dysfunction. A total of 44 patients were given a triple combination therapy of oral baricitinib 4 mg (up to 14 days), standard IV remdesivir regimen (up to 10 days), and IV dexamethasone 6 mg (up to 10 days). Overall, the results demonstrated that mortality was low (2.3%), with no need for invasive mechanical breathing in majority of patients (90%). The median length of hospitalization was 11 days whereas ICU stay was 6 days on an average, with a 9-day median recovery time. Adverse events were reported in 34% (15/44) patients. This was the first trial to demonstrate the safety and efficacy of a triple combination of baricitinib, remdesivir and corticosteroids in hospitalized COVID-19 patients. However, its primary weakness was the lack of a comparison group.

Through a non-randomized open label study in Greece, Gavriilidis et al. [49] analyzed the effect of various treatment modalities in the reduction of in-hospital mortality in 78 RT-PCR diagnosed COVID-19 patients. Participants were categorized into four groups: 26 patients received standard of Care (SOC) that included dexamethasone 6–8 mg OD, LMWH, antibiotic prophylaxis and supportive care, 11 patients received SOC and tocilizumab intravenously at a single dose of 8 mg/kg body weight (TOCI), 19 patients received SOC plus anakinra at a dosage of 200 mg BD for 3–6 days followed by 100 mg BD up to 10 days (ANA) and the COMBI group of 22 patients received a combination of tocilizumab, anakinra, dornase alfa (2500 IU/BD for 2 weeks) with budesonide (800 ug/BD) and salbutamol, and baricitinib at 4 mg OD if GFR >60 ml/min or 2 mg OD for 2 weeks. The baseline characteristics of all groups were similar. The SOC group observed 9 deaths (34.6%) and 10 intubations (38.5%) with a mean duration of hospital stay of 19.4 days, the ANA group had 6 deaths and intubations (31.6%) with an average duration of hospital stay of 23.9 days, the TOCI group showed 7 deaths (63.6%) and an average duration of 19.4 days of hospital stay and the COMBI group showed the lowest mortality of 2 deaths (9.1%, *P* = 0.014), lowest intubation rate (*P* = 0.013) and the lowest average hospital stay of 15.6 days (*P* = 0.019). Apart from these outcomes, the COMBI group also showed a prolonged survival (*P* = 0.003) after a median follow up of 110 days, an increase in ALC count (*P* = 0.021), and reduction in CRP levels (*P* = 0.002). Though the study demonstrates a reduction in mortality with the combination therapy including baricitinib, the lack of randomization and unequal group sizes are important limitations.

Wesley et al. [50] have published the results of an exploratory trial following the phase 3 COV-BARRIER trial which was a multicentric (18 centers across Argentina, Brazil, Mexico and the U.S.A.), randomized, double-blinded placebo controlled parallel group trial to compare the effect of baricitinib on all-cause mortality at day 28 and 60, overall improvement of clinical status, duration of hospitalization or time to recovery in COVID-19 patients. This study recruited 101 participants randomized 1:1 into baricitinib 4 mg or 2 mg if GFR < 60, l/min/1.73 m<sup>2</sup> (*n* = 51) and placebo (*n* = 50) for 14 days or up to discharge. All participants received the standard of care which included medications such as corticosteroids, antivirals, vasopressors, and prophylaxis for venous thromboembolic events as per local practice. All participants had at least one underlying comorbid condition. The median duration of treatment exposure was 12 days in the placebo group and 11 in the baricitinib group. The baricitinib group significantly reduced all-cause mortality by day 28 (39% in baricitinib vs 58% in placebo, HR 0.54, 95% CI 0.31–0.94., *P* = 0.03) with a 46% relative reduction and 19% absolute risk reduction, with a similar significant reduction at day 60 also (23 [45%] events vs 31 [62%]; HR 0.56 [95% CI 0.33–0.97]; *P* = 0.027; 44% relative reduction; absolute risk reduction 17%). The study revealed no significant differences in the number of ventilator free days or mean duration of hospitalization. Both groups showed a high proportion of treatment-emergent adverse events where 44 of 50 participants (88%) in the baricitinib group and 47 out of 49 (96%) in the placebo group reported at least one event, while 50% in the baricitinib arm and 71% of the placebo arm reported at least one serious adverse event, causing 28 and 35% of the patients to discontinue treatment in the baricitinib and placebo group respectively. There were five (10%) and three (6%) deaths due to adverse events in the baricitinib and placebo arm respectively. Overall, the study supported the results of the COV BARRIER trial by showing consistent results in reducing mortality in critically ill hospitalized patients with COVID-19 for baricitinib compared with placebo (plus standard of care, including corticosteroids), albeit in a small sample size.

Most recently, the results of ACTT-4 have been published (May 2022) [51], in which 1010 hospitalized patients with COVID-19 requiring supplemental oxygen or non-invasive mechanical ventilation were randomized to receive either baricitinib plus remdesivir (51%, *n* = 503) or dexamethasone plus remdesivir (49%, *n* = 482) at 67 sites across the world. All patients received remdesivir (≤10 days) and either baricitinib for a maximum of 14 days or dexamethasone for a maximum of 10 days. There was no difference between the two groups in the primary outcome of mechanical ventilation-free survival by day 29 [87.0% in the baricitinib plus remdesivir vs 87.6% in the dexamethasone plus remdesivir group; risk difference 0.6 (95% CI −3.6 to 4.8 and *P* = 0.91)]. Similar results were seen with odds ratio for improved clinical status at day 15 which was similar between the two groups. Outcomes were statistically similar for mortality at 29 days (2.9 vs 4.7% for baricitinib vs dexamethasone combination groups) or 60 days (6.8 vs 8%). Outcomes were consistently similar among different geographical regions, gender, race, and ethnicity as well. The safety analysis showed that 4% of patients in the baricitinib plus remdesivir group and 10% of patients in the dexamethasone plus remdesivir group experienced at least one treatment-related adverse event (risk difference: 60%; *P* = 000041). So, when combined with remdesivir, baricitinib is a significantly safer treatment option than dexamethasone, with severe or life-threatening grade 3 or 4 adverse events occurring in 28% of patients in the baricitinib plus remdesivir group compared to 36% of patients in the dexamethasone plus remdesivir group (*P* = 0012).
